Association between the Angle of the Left Subclavian Artery and Procedural Time for Percutaneous Coronary Intervention in Patients with Acute Coronary Syndrome

Background The effect of left subclavian artery tortuosity during percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) remains unclear. Methods Of 245 ACS patients (from November 2019 and May 2021), 79 who underwent PCI via a left radial approach (LRA) were included. We measured the angle of the left subclavian artery in the coronal view on CT imaging as an indicator of the tortuosity and investigated the association between that angle and the clinical variables and procedural time. Results Patients with a left subclavian artery angle of a median of <70 degrees (severe tortuosity) were older (75.4 ± 11.7 vs. 62.9 ± 12.3 years, P < 0.001) and had a higher prevalence of female sex (42.1% vs. 14.6%, P=0.007), hypertension (94.7% vs. 75.6%, P=0.02), and subclavian artery calcification (73.7% vs. 34.2%, P < 0.001) than those with that ≥70 degrees. The left subclavian artery angle correlated negatively with the sheath cannulation to the first balloon time (ρ = −0.51, P < 0.001) and total procedural time (ρ = −0.32, P=0.004). A multiple linear regression analysis revealed that the natural log transformation of the sheath insertion to first balloon time was associated with a subclavian artery angle of <70 degrees (β = 0.45, P < 0.001). Conclusion Our study showed that lower left subclavian artery angles as a marker of the tortuosity via the LRA were strongly associated with a longer sheath insertion to balloon time and subsequent entire procedure time during the PCI.


Introduction
Radial access percutaneous coronary intervention (PCI) is associated with a reduction in clinical adverse events in comparison to a femoral access in patients with acute coronary syndrome (ACS) [1][2][3][4][5]. Te right radial approach (RRA) is favored by many operators because of the ease of a standard access setup [6]. However, the RRA is also associated with technical difculties due to the right subclavian artery tortuosity in comparison to the left radial approach (LRA) [7]. Furthermore, arterial anatomic variations including the tortuosity of the right subclavian artery infuence the transradial procedural duration and outcomes [8,9]. Recent studies have shown that the use of a LRA in the management of ST-elevated myocardial infarction (STEMI) patients is associated with a comparable success rate and reperfusion times when compared with the RRA [6]. Terefore, the LRA can be an alternative approach to the RRA in some ACS patients, and it may be preferable for right-handed persons when considering the vascular complication risk. Although it is physically clear that the tortuosity of the left subclavian artery afects the passing of the wire and catheter or engaging the catheter, the data on the impact of the tortuosity of the left subclavian artery on the time required for the PCI in patients with ACS are lacking. Because it is well known that treatment delays are important determinants of patient outcome in patients with STelevation acute myocardial infarction (STEMI) [10] and some patients with non-STEMI (NSTEMI) [11], the identifcation of challenging cases through an LRA would be important. We hypothesized that the angular change in the left subclavian artery detected on chest computed tomography (CT) due to tortuosity infuences the time of the PCI using the LRA in patients with ACS. We, therefore, aimed to characterize the patients with severe tortuosity of the left subclavian artery and to investigate the association between the angular changes in the left subclavian artery and the time for the PCI.

Study Patients.
Tis was a retrospective observational study of 245 consecutive patients who underwent PCI for ACS with single-plane imaging at Nihon University Itabashi Hospital, Tokyo, Japan, between December 2019 and May 2021. Te study fow diagram is shown in Figure 1. Patients who had undergone a PCI via an LRA after a CT scan on admission were included in this study. In our hospital, an LRA is the frst-choice approach for coronary angiography or PCI unless there is a reason such as a lefthanded person, an arterial line being inserted, a paralyzed side, or a poor radial pulse on palpation. Te LRA included only a conventional and not a distal LRA. We did not consider CT to be necessary in all patients with ACS. However, this study was performed during the COVID-19 pandemic period. So, in our hospital, patients admitted to the hospital were subjected to a CT scan on admission as much as possible for the detection of mild or asymptomatic infections [12]. Patients who met any of the following criteria were excluded: (1) patients who had undergone a PCI via other arterial access approaches in such patients as those with dialysis; (2) recent myocardial infarction patients whose onset-time was from 2 to 28 days [13]; (3) patients who underwent a PCI to a non-native coronary vessel; (4) patients undergoing a physiological testing (instantaneous wave-free ratio/fractional fow reserve) guided PCI; (5) those in whom the PCI was terminated for any reason; and (6) other reasons, as shown in Figure 1. In this study, no patients had a history of left subclavian artery trauma. According to those criteria, of the 245 ACS patients, a total of 79 were included in this study. Te study protocol was approved by the Ethics Committee of Nihon University Itabashi Hospital (RK-201121-01) and was in accordance with the ethical standards of the institutional research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.  [14], and therefore, the angle of the left subclavian artery in the thorax was measured as an indicator of the tortuosity with the following method (Figures 2(a) and 2(b)). Te coronal plane image from the point where the bifurcation of the vertebral artery as a geographic landmark in the thorax was used for the measurement of the left subclavian artery. First, the coronal plane image that clearly identifed the left subclavian artery was chosen. Secondly, two points at least 5 mm away from each other were selected in the center of the blood vessel in the left subclavian artery. Tirdly, the angle of the line connecting the two points to the horizontal plane line was measured. Finally, the above measurements were repeated twice, and the lower angle was selected. Te angle of the left subclavian artery was estimated by two independent expert cardiologists who were not provided with the patients' clinical information. Two independent observers measured the angles of the left subclavian artery in the coronal CT in 25 randomly selected subjects to assess the interobserver reproducibility (intraclass correlation coefcients, 0.71), indicating a good reproducibility. A previous study indicated an association between the aortic root angle and success rates of transcatheter aortic valve implantations [15]. Te angle of the aortic root was also measured on the coronal plane CT as previously reported ( Figure 2(c)) [16].

Severity Assessment of the Coronary Artery Disease.
Te ACS included STEMIs, NSTEMIs, and unstable angina (UA) according to the 4th universal defnition of myocardial infarction [17]. Stenosis was considered signifcant if it was 75% according to the American Heart Association guidelines. A high-lateral culprit lesion was classifed as a left circumfex artery and a diagonal branch as a left anterior descending artery. Te defnition of the thrombolysis in myocardial infarction trial (TIMI) fow was graded as TIMI 0 � no perfusion, TIMI 1 � penetration without perfusion, TIMI 2 � partial perfusion, and TIMI 3 � complete perfusion, as described in the Phase I TIMI Trial [18].

Radial Artery Cannulation.
Radial artery punctures were performed with a dedicated radial cannulation needle and guidewire after local subcutaneous anesthesia with 1% lidocaine. A 6 French short hydrophilic sheath (Radifocus ® Introducer II, Terumo, Japan) was inserted, and 5000 IU of heparin was given.

Transradial Coronary Angiography and Percutaneous
Coronary Intervention. Te examination and treatment plan were based on the current guidelines [19]. For coronary angiography, the catheters to be employed were a 5 French Judkins right 4.0 (Goodtech, Nipro, Japan) for access to the right coronary artery and a 5 French Judkins left 4.0 (Goodtech, Nipro, Japan) for access to the left coronary (

Patient Characteristics.
Te patient characteristics are listed in Table 1. Te mean age was 68.9 ± 13.5, and 27.8% of the patients were female. Te frequencies of a history of hypertension and PCI were 84.8% and 15.2%, respectively. None of the patients had a history of a coronary artery bypass graft. In this study, STEMIs were the most frequent type of ACS (65.8%) and the left descending artery (LAD) was often the culprit lesion (43.6%). Not many patients had three-coronary vessel disease (35.4%). Te median time from sheath cannulation to the frst balloon time and total procedure time were 27.6 ± 13.1 min and 69.9 ± 39.6 min, respectively. All patients except for two had 3rd generation drug-eluting stents implanted. Te distribution of the angle of the subclavian artery in the coronal view was normally distributed, and the median value was 70 degrees (57, 77), and the mean was 68 ± 14 degrees ( Figure 3). According to the median value, the patients were divided into two groups including those with <70 degrees (n � 38) and those ≥70 degrees (n � 41), respectively ( 2%], P < 0.001) than the ≥70-degree patients. Tere was no diference in the angle of the aortic root between the two patient groups (45.5 ± 9.2 vs. 42.9 ± 7.9 degrees, P � 0.17). Regarding the PCI-related fndings, patients with <70 degrees exhibited a longer procedure time (81.3 ± 45.2 vs. 59.4 ± 30.5 min, P � 0.013) and sheath insertion to the frst balloon time (34.4 ± 14.1 vs. 21.4 ± 8.3 min, P < 0.001) than the ≥70 degree patients. In patients with culprit lesions of the right coronary artery (RCA) (n � 25), the patients with an angle of <70 degrees exhibited a longer sheath insertion to the frst balloon time (20.9 ± 8.9 vs. 12.7 ± 2.0 min, P � 0.009) and procedure time (55.5 ± 35.1 vs. 26.4 ± 7.1 min, P � 0.017) than the ≥70 degree patients. In patients with a culprit left coronary artery (LCA) (n � 54), the patients with an angle of <70 degrees also exhibited a longer sheath insertion to the frst balloon time (20.5 ± 8.5 vs. 12.9 ± 5.7 min, P < 0.001), but the procedural time did not signifcantly difer between the two patient groups (44.4 ± 20.1 vs. 38.6 ± 19.8 min, P � 0.30).

Associations between the Angle of the Subclavian Artery on the Coronal View and PCI-Related Parameters.
Te angle of the subclavian artery in the coronal view correlated negatively with the sheath insertion to the frst balloon time (ρ � −0.51, P < 0.001) and total procedural time (ρ � −0.32, P � 0.004) (Figures 4(a) and 4(b)). A creatinine assessment after the PCI was performed in all patients at 24 hours, 92% of the patients at 48 hours, and 95% of the patients at 72 hours. CIN occurred more frequently for an angle of the subclavian artery in the coronal view of <70 degrees (11 patients, 29.0%) than for ≥70 degrees (2 patients, 4.9%) (Odds ratio 7.78, 95% CI 1.64-38.74, P � 0.005) ( Figure 5).  Table 2. Tree-coronary vessel disease and a nonhighly experienced operator correlated with the sheath insertion to the frst balloon time. A pre-TIMI fow grade of 3 was more likely to be correlated with the sheath insertion and the frst balloon time. A multiple regression analysis revealed that the natural log transformation of the sheath insertion to the frst balloon time remained to be signifcantly associated with a lower angle of the subclavian artery on the coronal view (β � −0.38, P < 0.001) or an angle of the subclavian artery of <70 degrees (β � 0.45, P < 0.001) even after adjusting for the threecoronary vessel disease, nonhighly experienced operator, and a pre-TIMI fow grade of 3.

Discussion
Tis study had two major fndings: (1) a lower angle of the left subclavian artery was related to an older age, female sex, and the presence of hypertension in patients with ACS who underwent a left radial PCI; (2) a lower angle of the left subclavian artery have a moderate correlation with a longer sheath insertion to the frst balloon time and an incidence of CIN after the PCI, and it was independently associated with a longer sheath insertion to the frst balloon time even after the multivariate adjustment.

Te Factors and Clinical Importance Associated with the Angle of the Subclavian Artery in Patients with ACS.
Although it is well-known that a tortuous artery is associated with difculty and complications during catheterization procedures [23], measuring and reporting the tortuosity of an artery remains a challenging task in the absence of a standardized, universally accepted method [24]. In the most recent study, the right subclavian artery tortuosity has been defned as experimental manipulation difculty [25]. Measurements at the points of angulation of the intracerebral vasculature from magnetic resonance angiography images can partly evaluate the arterial tortuosity [26], and an experimental computational model has indicated that the angles difer as a result of the tortuosity [14]. Because the tortuosity of an artery is difcult to assess with angiography, those prior reports [14,26] have shown that our new method that quantitatively assesses the left subclavian artery angle on CT imaging is an indicator of the artery tortuosity. We do not believe that CT scans prior to cardiac catheterization are necessary for all patients with ACS. However, the angle assessment on CT imaging may provide a clinical advantage over the other modalities, especially in patients with ACS because ACS patients often undergo a CT prior to the PCI to detect and evaluate any aortic dissections or aortic aneurysms [27,28]. In addition, a CT scan taken previously would be informative, even if not immediately prior to the cardiac catheterization. Te RRA is widely used because of the associated ease and familiarity of the equipment manipulation, but the data regarding the LRA are lacking. We newly found that the left subclavian artery tortuosity as represented by a lower angle of the left subclavian artery was signifcantly associated with an older age, female sex, and the presence of hypertension. Cha et al. retrospectively investigated the factors associated with severe tortuosity in 2,341 consecutive patients who underwent an initial coronary angiography via the right radial artery. Teir study also showed that the clinical predictors of severe tortuosity of the right subclavian artery were hypertension, a female gender, an older age, and a short stature [25]. Terefore, although it has been expected, the clinical predictors of severe tortuosity may be similar regardless of a right or left subclavian artery.
Tere were only a few studies that have investigated the time from sheath insertion to the frst balloon time, fuoroscopy time, and total procedural time in a primary PCI for ACS, especially the LRA, because many studies have investigated the time from door to balloon time as an important factor in the treatment of STEMIs. Fu et al. investigated the efcacy of the LRA as compared to the RRA for a primary PCI in STEMI patients [20]. Teir sheath cannulation-to-balloon time via the LRA was 16.0 ± 4.8 minutes and contrast medium volume was 125.8 ± 19.6 mL, respectively. Although their contrast medium volume was similar to our results (136.7 mL), our sheath cannulation-to-balloon time was longer (27.6 ± 13.1). Te plausible reason for the slightly longer time in our study was that we confrmed the morphology of the lesion with IVUS before the frst balloon dilation as much as possible. Nonetheless, their study did not investigate the association between the clinical factors and sheath insertion to the frst balloon time via the LRA [20]. In patients with culprit lesions of the LCA, the procedural time did not signifcantly difer between an angle of the subclavian artery of <70 degrees and ≥70 degrees. Te plausible reason for the minimal efect of the angle on the procedural time was that the LCA included the LAD, which is longer than the RCA or circumfex artery and requires many stents. In our study, multiple stent implantations were more common in the patients with culprit lesions of the LCA than of the RCA (20 [37.0%] vs. 7 [28.0%], P � 0.43). Moreover, in the group with an LCA culprit, the prevalence of multiple stent implantations was less in the <70 degree than ≥70 degrees group (7 [ In this study, a univariate analysis showed that threecoronary vessel disease, not highly experienced operators, and a pre-TIMI fow grade 3 were more likely to be associated with a long sheath insertion to the frst balloon time; however, it was not evident for the potential factors such as diabetes, the lesion length, severe calcifcations, etc., which were derived from the data to explore the associated factors of the long fuoroscopy time [29] via mixed approaches including the radial artery, femoral artery, or rarely, the brachial artery. Although the exact explanation of those 3 associated factors was unclear, three-coronary vessel disease and a pre-TIMI fow grade 3 may be confounders of severe coronary disease and/or severe tortuosity, and a pre-TIMI fow grade 3 may be an inverse consequence of physicians having hurriedly performed the revascularization in patients who had a pre-TIMI follow grade of ≤2. More importantly, this study revealed that a lower angle of the left subclavian artery correlated signifcantly with a longer sheath insertion to the frst balloon time and procedure time, and it remained an independent factor of a longer sheath insertion to the frst balloon time. Tis implicated that the arterial tortuosity was strongly associated with the difculty not only in the manipulation while passing the wire and catheter or engaging the catheter but also to treat the coronary arteries themselves. Tis was suggested by the higher requirement of microcatheters for the culprit lesion wire crossing and the presence of subclavian artery calcifcations in patients with an angle of the left subclavian artery of <70 degrees.
Our study also showed that patients with an angle of the left subclavian artery of <70 degrees had a risk of an incidence of CIN. Several risk factors for CIN are associated with atherosclerosis [30]. Terefore, the angular changes in the left subclavian artery are considered to be the representation of those risk factors on the CT image.  [25]. Terefore, physicians should more carefully manipulate the catheters and exchange the guidewires or catheters, and they should not apply undue force in such patients in order to prevent severe vascular complications. A lower angle of the subclavian artery with the risk of a longer procedure time is valuable in patients with ACS who are sometimes hemodynamically unstable because it is helpful for deciding whether to administer mechanical support and invasive ventilation before the revascularization. In the patients with an angle of the left subclavian artery of <70 degrees, the incidence of CIN was signifcantly higher than in the ≥70 degrees group, so contrast medium should be minimized to prevent contrast nephropathy.

Limitations
Tere were several limitations to our study. First, the present study included a small size and single-center sample. Second, this was a retrospective study of patients who were selected for the LRA. Terefore, the analysis did not include dialysis patients or a group of patients whose radial artery was not touched, who were considered to have a higher degree of atherosclerosis than the subjects in this study. Tird, the CT images were taken when the patient's hands were positioned above the head, so it should be considered that our angle measurements were obtained under this patient's position. Finally, patients who did not undergo CT scans before the PCI were not applicable. Nonetheless, we found signifcant associations between a lower angle of the left subclavian artery and being female, a low height, and hypertension, and thus, such factors may help identify patients who have the potential risk for a long sheath insertion before the frst balloon time.

Conclusion
Our study showed that lower angles of the left subclavian artery as a marker of the tortuosity via an LRA were strongly associated with a longer sheath insertion time to the frst balloon time and subsequent entire procedure time during the PCI.

Data Availability
Te data used to support the fndings of this study are available from the corresponding author upon request.

Ethical Approval
Te study protocol was approved by the Ethics Committee of Nihon University Itabashi Hospital (RK-201121-01).